In most species, including man, the physiological glucocorticosteroid is cortisol (hydrocortisone). Glucocorticosteroids are secreted in response to ACTH (corticotropin), which shows both circadian rhythm variation and elevations in response to stress and food. Cortisol levels are responsive within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol is a glucocorticosteroid and acts by binding to an intracellular, glucocorticoid receptor (GR). In man, glucocorticoid receptors are present in two forms: a ligand-binding GR-alpha of 777 amino acids; and a GR-beta isoform which lacks the 50 carboxy terminal amino acids. Since these include the ligand binding domain, GR-beta is unable to bind ligand, is constitutively localized in the nucleus, and is transcriptionally inactive. The glucocorticoid receptor, GR, is also known as the glucocorticoid receptor II, or GRII.
The biologic effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level using receptor modulators, such as agonists, partial agonists and antagonists. Several different classes of agents are able to block the physiologic effects of GR-agonist binding. These antagonists include compositions which, by binding to GR, block the ability of an agonist to effectively bind to and/or activate the GR. One such known GR antagonist, mifepristone, has been found to be an effective anti-glucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to the GR with high affinity, with a dissociation constant (Kd) of 10−9 M (Cadepond (1997) Annu. Rev. Med. 48:129).
In addition to cortisol, the biological effects of other glucocorticosteroids can be modulated at the GR level using receptor modulators, such as agonists, partial agonists and antagonists. When administered to subjects in need thereof, glucocorticosteroids can provide both intended therapeutic effects as well as undesirable side effects. The beneficial therapeutic effects are normally considered to be the result of GR induced gene transrepression, while most of the undesirable side effects are associated with GR induced gene transactivation. What is needed in the art are new compositions and methods for ameliorating the negative side effects of glucocorticosteroids by inhibiting chronic glucocorticoid receptor induced transactivation while not significantly reducing the intended therapeutic effects afforded by glucocorticoid receptor induced transrepression. Surprisingly, the present invention meets these and other needs.